Sustained release therapeutic compositions

ABSTRACT

Shaped pharmaceutical tablets, lozenges, suppositories and other solid dosage unit forms which have a prolonged and regular release pattern of a therapeutically active medicament incorporated therein, wherein the shaped dosage unit comprises a carrier base material of hydroxypropylmethylcellulose or a mixture thereof with up to 30% ethylcellulose and/or up to 30% sodium carboxymethylcellulose and wherein the carrier base material is subjected to hydrolysis and oxidation so as to generate thereon a desired minimum concentration of carbonyl and carboxyl groups, and then admixed and shaped with a therapeutically active medicament.

BACKGROUND OF THE INVENTION

Commercially available hydroxypropylmethylcelluloses contain 19-30weight-% methoxy content and 4-32 weight-% hydroxypropyl content and areknown as Methocel cellulose ethers (Dow Chemical Co.). Ethylcelluloseand sodium carboxymethylcellulose are also well known and readilyavailable.

Methocel has been used in the prepartion of buccal or sublingualproducts for transmucosally acting medicaments, as described in BritishPat. No. 1,171,691 and 1,279,214 and U.S. Pat. No. 3,870,790. Methocelhas been considered to be lacking in the most desirable properties formaking compressed long lasting troches and as a result dry skim milkpowder combined with Guar gum has been substituted (U.S. Pat. No.3,590,117). Carboxypolymethylene and sodium caseinate have also beenused for the same purpose (U.S. Pat. No. 3,594,467). While it is knownthat buccal or sublingual lozenges and tablets intended to be swallowedcan be made with various active agents and carriers, where steadyprolonged medication is required and a regular rate of release is neededwith good absorption of medicament, no fully satisfactory carrier hasbeen heretofore been produced. The present invention is directed towardimprovements in a carrier base for use in the preparation of orallybuccaly or sublingually etc. administered lozenges and tablets as wellas suppositories which have a regular and prolonged release pattern fora systemically absorbable medicament or active ingredient incorporatedtherein.

THE PRESENT INVENTION

According to the present invention, it has now been discovered thatimportant advantages and improvements over prior products containingMethocel, as described in U.S. Pat. Nos. 3,594,467 and 3,870,790 andBritish Pat. Nos. 1,171,691 and 1,279,214, can be obtained by specialtreatment thereof under controlled conditions so as to chemically modifythe structure as a result of hydrolysis and oxidation, prior toincorporation of active medicament therein, and thus the inherentlydesirable properties of Methocel can be taken advantage of in asignificantly improved sustained continuous release compressed lozenge,tablet or suppository capable of providing steady therapeutic bloodlevels. The present invention therefore subjectshydroxypropylmethylcellulose to conditions which promote hydrolysis andoxidation thereby producing a chemically modified carrier materialhaving about the same molecular weight but a unique chemical structurehaving greater stability, reduced water solubility, less likelihood ofimpaction as well as being bland, and non-irritating. The chemicallymodified hydroxypropylmethylcellulose carrier material is characterizedby a carbonyl content of at least 0.2 grams/100 grams and a carboxylcontent of at least 0.37 grams/100 grams. The carbonyl content may rangefrom 0.2 to 3.0 grams/100 grams with a preferred carbonyl content of0.2-2.0 grams/100 grams. The carboxyl content may range from 0.37 to2.60 grams/100 grams.

The hydroxylpropylmethylcellulose used as the starting material for thepresent invention is known and commercially available as Methocel E-50(Dow Chemical Co.) which is a premium grade found best forpharmaceutical products. This Methocel cellulose ether has a methoxylcontent of 28-30 weight-% which represents a methoxyl degree ofsubstitution of 1.8-2.0 and a hydroxypropyl content of 7.5-12 weight-%which represents a molar substitution of 0.20-0.31.

The hydroxypropylmethylcellulose can be optionally mixed with about 0 to30% by weight of the mixture of ethylcellulose and/or about 0 to 30% ofsodium carboxymethylcellulose. Thus, the hydroxypropylmethylcellulosecontent of the carrier base can range from 40 to 100%. Thehydroxypropylmethylcellulose may be processed alone and then mixed inpowder form with ethylcellulose and/or sodium carboxymethylcellulose.Alternatively, a mixture of hydroxypropylmethylcellulose withethylcellulose and/or sodium carboxymethylcellulose is subjected inpowder form to the hereinafter described processing steps. After thematerials are processed as described, an active ingredient in suitableamount to provide an effective unit dose per lozenge, tablet orsuppository is incorporated therein.

The active ingredient can be of any type of medication which actssystemically and can be administered orally to transmit the activemedicament into the gastrointestinal tract and into the blood stream intherapeutically effective levels without early excessive peakconcentrations, without being inactivated by physiological fluids andwithout passing unchanged through the body of the patient or subject bybeing excreted unabsorbed. Alternatively, the active ingredient can beof any type of medication which acts through the buccal tissues of themouth to transmit the active ingredient directly into the blood streamthus by-passing both any possible first pass liver metabolism or thegastric and intestinal fluids which often have an adverse inactivatingor destructive action on many active ingredients unless they arespecially protected against such fluids as by means of an entericcoating or the like. The active ingredient can also be of a type ofmedication which can be transmitted into the blood circulation throughthe rectal tissues.

Representative active medicaments include antacids, anti-inflammatorysubstances, coronary dilators, cerebral dilators, vasodilators,antibacterials, psychotropics, antimanics, stimulants, antihistamines,laxatives, decongestants, vitamins, etc. However, it is to be understoodthat the invention is applicable to sublingual lozenges, suppositoriesand compressed tablets, the latter being intended to be swallowed inunit dosage form and which upon ingestion according to a prescribedregimen give slow and regular release of active medicament without aninitial dumping of a fixed percentage in the intestinal tract whilebeing protected against normally inactivating gastric fluids.

The chemically modified hydroxypropylmethylcellulose alone or with up to30% of ethylcellulose by weight and/or with up to 30% of sodiumcarboxymethylcellulose by weight, forms what is herein called along-acting slow dissolving carrier of such nature that it has aprotective, demulcent and buffering effect in the body and causes theactive medicament to exert its optimum therapeutic action immediatelyand incrementally for up to several hours so that full therapeuticadvantage can be taken of the entire or substantially the entire amountof active medicament administered. This unexpectedly high degree ofefficiency is a particular advantage of the invention and minimizes sideeffects of the medication.

The chemically modified hydroxypropylmethylcellulose of the presentinvention is prepared by exposing the cellulose ether successively orconcurrently to hydrolyzing and oxidizing conditions.

The hydrolysis may be carried out by placing the Methocel in ahumidifying chamber and exposing it to high humidity conditions at roomor elevated temperatures. Typically, when the humidity of the chamberreaches at least 85%, the material is maintained under this humidity forat least 12 hours. Alternatively, the Methocel is mixed with water, e.g.50-100% of its weight of water, and heated at a temperature of 30°-100°C. for at least 12 hours. The temperature may be varied over a widerange. The optimum time, temperature and water content of the reactionmixture are determined by the available equipment.

After the hydrolysis of the Methocel has been carried out, the productis subjected to oxidation. In one method, the product is heated in anoven at about 30° to 50° C., while a stream of oxygen or forced air ispassed over the polymer. In another method, the hydrolyzed Methocel isplaced in a vertical tube or tower and air or oxygen which has beenmixed with water or steam or has been passed through water at room orelevated temperature and then reheated, if necessary, to a temperatureof at least 30° C., is passed upwards through the Methocel. Ifnecessary, the tower is heated to maintain the temperature of about 30°C. to 50° C. The passage of air is continued for at least 5 hours anduntil chemical analysis indicates that the desired carbonyl and carboxylcontents have been obtained.

In an alternative method, the hydrolysis and oxidation reactions may becarried out in one step by subjecting the hydroxypropylmethylcelluloseto treatment with air or oxygen containing a sufficient amount of water,at an elevated temperature, e.g. in a fluid bed process.

The carbonyl content of the polymer is determined by adding a knownamount of a solution of hydroxylamine in 1N NaOH to the polymer sample.After 2 hours at 50° C., the mixture is cooled to room temperature,distilled water is added and the mixture is stirred until all thematerial has dissolved. An aliquot of the solution is then titrated with0.1N HCl to a pH of 3.2 to determine the amount of unreacted base.

The carboxyl content of the polymer is determined by stirring the samplein distilled water and then adding 0.1N NaOH. The mixture is stirreduntil all of the sample has dissolved and then the excess base istitrated with 0.1N HCl using phenolphthalein as indicator.

The untreated hydroxypropylmethylcellulose generally has a carbonylcontent below 0.9 gram/100 grams and a carboxyl content below 0.36gram/100 grams. After hydrolysis and oxidation, the carbonyl content isin the range of 0.2-3.0 grams/100 grams and the carboxyl content is inthe range of 0.37-2.6 gram/100 grams.

The moisture content of the chemically modifiedhydroxyproplmethylcellulose is generally in the range of 0.5-10%. Ifnecessary, it may be brought to this level by additional forced airheating, by the passage of heated air over or through the material or byheating in vacuo. The attainment of a moisture content in the desiredrange without oxidation yields an unsatisfactory product. Thus, ifMethocel E-50 is subjected to high humidity for an extended period oftime and the wet and/or hydrolyzed Methocel then undergoes drying invacuo in the absence of air, the carboxyl content of the product isbelow the desired level and the product does not possess the desirableor acceptable performance characteristics when used as a carrier in thepreparation of a sustained release therapeutic composition.

When the required carbonyl and carboxyl contents are attained, thechemically modified hydroxypropylmethylcellulose is passed through a No.2 stainless steel screen employing a Fitzpatrick Comminuter having itsknives directed forward and operating at medium speed.

The hydrolysis-oxidation treatment may be applied to a mixture ofhydroxypropylmethylcellulose and up to 30% ethylcellulose and/or up to30% sodium carboxymethylcellulose. In this case, after the moisturecontent has been reduced to the 0.5-10% range, the comminution step maybe omitted since the material is free flowing and powdery. The moisturecontent of the carrier plays a role in the preparation of shapedcarrier-medicament compositions and influences the integrity of theproduct.

By way of example, in making up tablets containing an orallyadministrable systemically absorbable active component such as one ofthe heretofore mentioned medicaments, the treated oral carrier materialis thoroughly intermixed with the medicament which is also in powderedor granular form and any other needed ingredients which are conventionalin tablet making such as magnesium stearate, lactose, starch and, ingeneral, binders, fillers, disintegrating agents, and the like. Thecomplete mixture, in an amount sufficient to make a uniform batch oftablets, such as 50,000, of which each contains an effective amount ofactive medicament, is then subjected to tableting in conventionaltableting machines but at, for example, compression pressures of 4 to 15kg/in.² and because of the use of the specially processed carriermaterial in the production of the tablets, a product is obtained whichhas a desired set of properties such as predetermined prolonged actionand a regular delayed release pattern so that the medicinal agent oractive ingredient is available over a period of 1-12 hours depending onthe precise tablet size and hardness and the particular carrier mixture.In this way it is possible to produce sustained or slow continuousrelease tablets in relatively simple and economical manner on acommercial scale as contrasted with the more elaborate and more complexmaterials and procedures heretofore employed or proposed.

Procedures for preparing the chemically modifiedhydroxypropylmethylcellulose or mixtures thereof with ethylcellulose orsodium carboxymethylcellulose are illustrated by the following exampleswhich are non-limiting and can be modified so as to utilize otherequipment or procedures for hydrolysis and/or oxidation which are wellknown to those skilled in the art.

EXAMPLE NO. 1

Hydroxypropylmethylcellulose (Methocel E-50) or a mixture ofhydroxypropylmethylcellulose with ethylcellulose and/or sodiumcarboxymethylcellulose is introduced into a heating chamber providedwith an exhaust which is at that time in closed or shut position andwhich chamber is provided with a heating unit and a forced air blowerwhich is inoperative at this stage of the procedure in that the heat andforced air are only applied at a subsequent stage. The carrier materialto be processed is placed in thin layers (not more than 1/4" thick) ontrays of the chamber which are lined with heat-resistant parchment paperand the trays are placed on racks in the oven chamber using onlyalternate shelves thereby providing adequate spacing between the layersof carrier material being treated. There is then placed within the ovenchamber a humidifier equipped with a humidistat which is preset tomaintain humidity in the oven chamber at about 85%, the humidifier beingfilled with sufficient distilled or deionized water to last for 24 to 36hours.

The humidifier employed is Arvin Model 50 H 42 (Sears Roebuck)--10gallon capacity having low and high air speeds and the humidistat isprovided with nine settings for moisture control. In the present examplethe humidistat is set to position 7 which maintains 85-90% humidity inthe oven chamber per 250 cubic feet of airflow and a temperature ofapproximately 75° F. (24° C.).

The humidifier is activated and the heating chamber is closed. Theprocess is allowed to proceed under 85-90% humidity for 24 hours. Thehumidifier is then removed from the heating chamber, the exhaustaperture opened by manipulation of the valve, and the forced air bloweris activated so as to apply heat at a temperature of 110°-120° F.(43°-49° C.). At the end of 12 hours the carbonyl and carboxyl contentsof the treated material are checked by removing and analyzing a sample.

The carbonyl and carboxyl contents of the treated material are 1.34 and0.54 grams/100 grams, respectively, whereas the untreated celluloseether has carbonyl and carboxyl contents of 0.56 and 0.33 grams/100grams, respectively.

The treated material is removed from the oven and passed through a No. 2stainless steel screen employing a Fitzpatrick Comminuter at mediumspeed.

EXAMPLE NO. 2

A 1000 gram batch of Methocel E-50 was mixed with 1000 grams of water ina Waring Blender. The mixture was placed in a glass jar which was closedwith a canning lid containing a self-sealing rubber gasket. The jar waskept in an oven at 90° C. for 24 hours to effect hydrolysis.

The hydrolyzed Methocel was transferred to a vertical cylinder which waswrapped with heating tape so as to maintain a bed temperature at about50° C. Air was pumped into a flask containing water at 60° C., thenthrough copper coils immersed in a 50° C. water bath and then into thebed of polymer. The hot, wet air entered at the bottom of the bed ofpolymer, and by means of a manifold which permitted the air to enter thepolymer bed at four points through perforated tubes, passed upwardthrough the bed as a finely dispersed gas stream. The oxidation wascarried out for 24 hours at 50° C.

Samples of the untreated, hydrolyzed and oxidized Methocel E-50 weredried in vacuo to constant weight and subjected to analysis. The resultswere as follows:

    ______________________________________                                                      Carbonyl      Carboxyl                                                        content,      content,                                          Methocel E-50 g/100 g       g/100 g                                           ______________________________________                                        Untreated     0.80          0.34                                              Hydrolyzed    1.95          0.40                                              Oxidized      1.59          0.89                                              ______________________________________                                    

The viscosities of 2% aqueous solutions of the untreated, hydrolyzed andoxidized materials at 25° C. were essentiall the same, indicating thatthe hydrolysis and oxidation reactions did not result in chain cleavageand there was no reduction in molecular weight of the cellulose ether.

Compositions containing the chemically modifiedhydroxypropylmethylcellulose are illustrated in non-limiting ExamplesNo. 3-16, wherein "Synchron Carrier" refers to the carrier base preparedby the process described in Example No. 1 and having the carbonyl andcarboxyl contents indicated therein.

EXAMPLE NO. 3 Demulcent and Adsorbent

A demulcent and adsorbent lozenge was prepared from the followingingredients in the following relative proportions.

    ______________________________________                                        Ingredients               mg/tablet                                           ______________________________________                                        1     Synchron Carrier        232                                             2     Gastric mucin           25                                              3     Aluminum hydroxide gel dried granular                                                                 250                                             4     Magnesium trisilicate granular                                                                        250                                             5     Methyl paraben U.S.P.   0.8                                             6     Propyl paraben U.S.P.   0.08                                            7     Felcofix cherry flavor No. 1265                                                                       16                                              8     Syloid 244 (Silica aerogel)                                                                           5                                               9     Carbowax 6000W          6.81                                            10    Stearic acid            8.0                                             ______________________________________                                    

Using the foregoing ingredients, a batch weighing 793.69 g was preparedby weighing out ingredients 1-4, screening ingredients 5-10 and mixingand blending all ingredients for 20 minutes following which they weresubjected to compression in a tableting machine having a 1/2" die sizeand a 1/2" punch to make tablets with an average weight of 0.794 g and athickness of 0.210"±0.01". The hardness of the tablet was 11-13kg/square inch.

EXAMPLE NO. 4 Analgesic

    ______________________________________                                        Ingredients             mg/tablet                                             ______________________________________                                        1       Aspirin powder U.S.P.                                                                             525.0                                             2       Synchron Carrier    325.5                                             3       Glycine             45.0                                              4       Syloid 244 (Silica aerogel)                                                                       4.5                                               ______________________________________                                    

Ingredients 1, 2 and 3 are mixed in a bowl into which ingredient 4 isadded after screening and the whole blended for 20 minutes andcompressed in the manner described in Example No. 3. Each tablet weighed0.9 g.

EXAMPLE NO. 5 Antihistamine

    ______________________________________                                        Ingredients              mg/tablet                                            ______________________________________                                        1      Chlorpheniramine maleate U.S.P.                                                                     12.60                                            2      Synchron Carrier      509.20                                           3      Methyl paraben U.S.P. 0.52                                             4      Propyl paraben U.S.P. 0.06                                             5      Syloid 244 (Silica aerogel)                                                                         2.63                                             ______________________________________                                    

Ingredient 2 was placed in a suitable bowl or container and ingredients1,3, 4 and 5 were weighted out and added after screening and the wholeblended for 20 minutes following which the compression into tablets tookplace on a tableting machine using a die size of 7/16" with a punch of7/16" to obtain a tablet thickness of 0.250"±0.01" with a tablethardness of 11-13 kg/square inch. Each tablet weighed 0.525 g.

EXAMPLE NO. 6 Appetite Satient

    ______________________________________                                        Ingredients               mg/tablet                                           ______________________________________                                        1      Synchron Carrier       60.0                                            2      Benzocaine             9.9                                             3      Saccharin              0.3                                             4      Felcofix peppermint    1.5                                             5      Felcofix cherry flavor No. 1265                                                                      2.5                                             7      Carbowax 6000W         0.4                                             7      Syloid 244 (Silica aerogel)                                                                          0.4                                             8      Methyl paraben U.S.P.  0.075                                           9      Propyl paraben U.S.P.  0.0075                                          ______________________________________                                    

Ingredient 1 was placed in a stainless steel bowl as in the previousexamples and ingredients 2-9 were also weighed out and screened and allingredients thoroughly mixed and blended in a bowl for 20 minutesfollowing which they were compressed into tablets on a tableting machinehaving a die size of 7/32" and a punch of 7/32" to form tablets having athickness of 0.110" and a hardness of 7-10 kg/square inch. Each tabletweighed 0.075 g.

EXAMPLE NO. 7 Laxative

    ______________________________________                                               Ingredients      mg/tablet                                             ______________________________________                                        1        Phenolphthalein U.S.P.                                                                           33.00                                             2        Synchron Carrier   513.64                                            3        Methyl paraben U.S.P.                                                                            0.55                                              4        Propyl paraben U.S.P.                                                                            0.06                                              5        Syloid 244 (Silica aerogel)                                                                      2.75                                              ______________________________________                                    

Ingredients 1 and 2 were placed in a stainless steel bowl to which afterscreening were added ingredients 3, 4 and 5 and the whole blended for 20minutes and compressed as in Example No. 5. The tablet thickness was0.250"±0.01" and the hardness was 10 kg/square inch. Each tablet weighed0.55 g.

EXAMPLE NO. 8 Laxative

    ______________________________________                                               Ingredients      mg/tablet                                             ______________________________________                                        1        Phenolphthalein U.S.P.                                                                           66.0                                              2        Synchron Carrier   480.64                                            3        Methyl paraben U.S.P.                                                                            0.55                                              4        Propyl paraben U.S.P.                                                                            0.06                                              5        Syloid 244 (Silica aerogel)                                                                      2.75                                              ______________________________________                                    

The same procedure was followed as in Example No. 7 with the sameresults.

EXAMPLE NO. 9 Breath Wafers

    ______________________________________                                        Ingredients               mg/tablet                                           ______________________________________                                        1     Synchron Carrier        629.9                                           2     Sorbitol                37.5                                            3     Mannitol                37.5                                            4     Sodium bicarbonate U.S.P. granular                                                                    15.0                                            5     Stearic acid            15.0                                            6     Syloid 244 (Silica aerogel)                                                                           7.5                                             7     Oil of peppermint U.S.P.                                                                              3.8                                             8     Oil of wintergreen U.S.P.                                                                             3.8                                             ______________________________________                                    

Ingredients 1-5 were placed in a stainless steel bowl, ingredients 7 and8 were adsorbed on ingredient 6 and screened and added to the stainlesssteel bowl. All ingredients were mixed and blended for 20 minutes andcompressed as previously described except that the tablets were in waferform with a thickness of 0.175"±0.01" with a hardness of 8-10 kg/squareinch. Each tablet weighed 0.75 g.

EXAMPLE NO. 10 Decongestant

    ______________________________________                                        Ingredients             mg/tablet                                             ______________________________________                                        1      Synchron Carrier     728.5                                             2      Sorbitol             42.5                                              3      Mannitol             42.5                                              4      Stearic acid         17.2                                              5      Menthol              4.3                                               6      Oil of Eucalyptol    2.1                                               7      Camphor              4.3                                               8      Syloid 244 (Silica aerogel)                                                                        8.6                                               ______________________________________                                    

Ingredients 1-4 were screened and placed in a stainless steel bowl,ingredients 5, 6 and 7 were triturated until they became liquid and thenadsorbed on ingredient 8. The mixture was screened into the otheringredients which had already been placed into the stainless steel bowland blended and compressed as previously described. The tablets had athickness of 0.220"±0.01" and a hardness of 8-10 kg/square inch. Eachtablet weighed 0.85 g.

EXAMPLE NO. 11 Vitamin

    ______________________________________                                        Ingredients             mg/tablet                                             ______________________________________                                        1      Ascorbic acid U.S.P. powder                                                                        105                                               2      Synchron Carrier     691                                               3      Syloid 244 (Silica aerogel)                                                                         4                                                ______________________________________                                    

Ingredients 1 and 2 were weighed out as in the preceding examples andplaced into a stainless steel bowl into which ingredient 3 was addedafter screening and the whole blended for 20 minutes and compressed aspreviously described. The tablets had a thickness of 0.210"±0.01" and ahardness of 11-13 kg/square inch. Each tablet weighed 0.8 g.

In Examples No. 12-16 the quantities shown are utilized in thepreparation of 50,000 dosage units and the blending and tableting arecarried out as previously described.

EXAMPLE NO. 12 Vasodilator

    ______________________________________                                        Nitroglycerin         325 g.                                                  Beta Lactose          2,975 g.                                                Syloid No. 244        50 g.                                                   Cherry flavor         100 g.                                                  Synchron Carrier      23,750 g.                                               ______________________________________                                    

EXAMPLE NO. 13 Anti-inflammatory

    ______________________________________                                        Prednisolone          250 g.                                                  Synchron Carrier      9,465 g.                                                Syloid No. 244        50 g.                                                   Cherry flavor         100 g.                                                  ______________________________________                                    

EXAMPLE NO. 14 Anti-Manic depressive

    ______________________________________                                        Lithium Carbonate     15,000 g.                                               Synchron Carrier      19,880 g.                                               Syloid No. 244        10 g.                                                   Cherry flavor         15 g.                                                   ______________________________________                                    

EXAMPLE NO. 15 Antacid

    ______________________________________                                        Aluminum Hydroxide Gel  12,500 g.                                             Magnesium Glycinate     12,500 g.                                             Gastric Mucin           5,000 g.                                              Carbowax 6000 W         34.5 g.                                               Synchron Carrier        12,000 g.                                             Syloid No. 244          250 g.                                                Cherry flavor           500 g.                                                ______________________________________                                    

EXAMPLE NO. 16 Antibiotic

    ______________________________________                                        Ampicillin            12,500 g.                                               Synchron Carrier      2,500 g.                                                Syloid No. 244        30 g.                                                   Cherry flavor         25 g.                                                   ______________________________________                                    

In our earlier U.S. Pat. No. 3,870,790 it was disclosed that the use ofa premoisturized hydroxypropylmethylcellulose powder having a moisturecontent of from about 5 to about 25% in the preparation of a compressedsolid dosage unit containing an active therapeutic ingredient, gavesustained release compositions. The release was controlled by theincreased compression or higher degree of compression pressure permittedby the presence of the indicated amount of moisture.

In the present invention, it has been found that a significantly greatercontrol of the release pattern is achieved by a chemical modificationwhich results in an increase in carboxyl functionality in thehydroxypropylmethylcellulose molecule. Although the actual mechanism isnot known, it may be speculated that the slower release rate arises froma decreased rate of swelling or a lower water solubility resulting froma hydrogen-bonding interaction between the carboxyl and the carbonyland/or hydroxyl groups in the hydroxypropylmethylcellulose which hasbeen subjected to both hydrolysis and oxidation.

In contrast to the disclosure of U.S. Pat. No. 3,870,790 it has now beenfound that moisture contents as low as 0.5% can be present during thepreparation of tablets and other compressed solid shapes. The amount ofmoisture present influences the amount of pressure necessary to preparethe shaped objects and the integrity thereof but plays a minor role ascompared to the chemical structure in the rate of release of medicamentsfrom the chemically modified hydroxypropylmethylcellulose. Similarly,while the release pattern is governed at least in part by the size ofthe tablet or other shaped object as well as by the degree ofcompression, the chemical structure of the hydroxypropylmethylcellulosewhich has been subjected to chemical modification superimposes itseffect and is the dominant factor in the control of the release rate.

It should be noted that the improvement in release characteristics hasbeen attained by treating the same hydroxypropylmethylcellulose usedearlier. Thus, while U.S. Pat. No. 3,870,790 refers to Methocel HG 60and the present invention refers to Methocel E-50, these are the samematerials, the manufacturer having changed the designation in theinterim.

The release pattern of active medicament from the new carrier can becontrolled according to the particular medication and its intendedtherapeutic effect. For a sublingual lozenge or tablet the releasepattern may be varied from about 1/4 hour to 4 hours. For orallyadministered tablets, the rate of release may be 4-8 hours or 8-10hours, as desired, and this has been confirmed by X-rays with bariumsulfate to show the motility and disintegration of the tablet as itproceeds down the intestinal tract. For vaginal and rectalsuppositories, the release pattern ranges from 12 to 36 hours, althoughof course, it can be less where indicated. Predetermined releasepatterns of unusually reliable and constant characteristics can besecured. This is often very important medically, especially whentreating patients having coronary diseases, such as angina pectoris aswith nitroglycerin, or related problems of circulatory disorders orabnormal blood pressure conditions or psychotropic/manic depressiveschizophrenia. The invention is particularly important also in treatingsuch conditions as ulcerated tissue or mucous lesions and otherconditions arising from local hyperacidity or metabolic dysfunction inthe physiological system. The invention is, therefore, of very versatileand adaptable nature giving it a wide scope of application and end use.

The foregoing is exemplary of compositions and products responding tothe present invention, but it is to be understood that they areillustrative and not limitative since many active ingredients of varioustypes can be employed in the new long-lasting carrier so long as theyare absorbable into blood or tissue from the general intestinal tract,etc. The invention is also intended to cover other dosage forms or formsfor application of sustained release ingredients such as vaginal andrectal suppositories. The lozenges and tablets particularly act on oral,oropharyngeal and pharyngeal regions. The total dosage is governed byusual medical considerations or physicians' directions and whensufficiently large doses of active medicament are incorporated in theunit dosage form, systemic as well as local action is obtained toovercome or control the pathological condition or disorder beingtreated.

The presence of a stabilizing agent in the oral carrier tends to preventundesired changes in the carbonyl and carboxyl contents during shippingand storage. A reducing agent such as ascorbyl stearate or palmitate orsodium metabisulfite may be added to the carrier material to inhibitoxidation. The stabilizer or reducing agent is usually added after thehydroxypropylmethylcellulose has been subjected to thehydrolysis-oxidation treatment, in a concentration of 0.1-1.0% of theweight of the carrier material.

In evaluating drugs incorporated in the oral carrier system or base ofthe present invention, it is important to understand the factorsinfluencing the absorption and therapeutic effectiveness of drugproducts in compositions responding hereto. Under usual circumstances,disintegration of a tablet into small particles in the gastrointestinalfluids speeds dissolution because of much increased surface area of thedrug. Consequently, absorption is more rapid and the duration oftherapeutic action depends primarily upon the rate of absorption. Therate and extent of drug absorption thus can influence both the durationof action and the efficacy of drug therapy. It follows that the fasterthe absorption, the earlier peak level of drug is reached but ifabsorption is too slow, the concentration of drug in blood and tissuesbut never reach therapeutic levels. Subsequent to absorption, there is adrop in concentration that depends in large part upon elimination and/ormetabolism.

Drugs embedded in the present "Synchron" Carrier System, as I term thecarrier base, are intended to attain and maintain a steady concentrationof drug in blood or tissues. One objective in using these preparationsis to reduce the dosage frequency, to make therapy simple andconvenient, and to improve compliance by the patient. In addition, bymaintaining a reasonably constant plasma concentration of drug,excessive or premature peaking is avoided and side effects, which may beassociated with peak concentrations of drug, would be lessened. Inaddition, a more uniform concentration of drug in blood and tissues ismuch more likely to be paralleled by a more uniform pharmacologic effectand response. With disolution being the main rate-limiting step in drugabsorption, the rate of solution of the drug from the dosage form intothe surrounding fluids at the absorption site is controlled by thechemical changes induced during production of the "Synchron" CarrierSystem. With the "Synchron" Carrier System the drug can further bereleased to a specific site at a uniform rate independently of the pHenvironment, resulting in steady concentrations of the drug in tissues.Drugs incorporated into the "Synchron" Carrier System vehicle are proneto be absorbed completely, but more slowly, and are formulated tomaintain the therapeutic effective level of the particular drug and toproduce a prolonged response and a diminished rate of unassimilated drugelimination.

The absorption data may be determined and expressed as the cumulativepercentage of the dose absorbed plotted against time, or analyzedfurther to derive information as to the kinetics of the absorptionprocess. Usually the total body clearance of a drug is fixed. Then thetotal area under the plasma concentration-time curve is proportional tothe dose absorbed and independent of the rate of absorption. Areaanalysis forms the basis for estimation and comparison of the extent ofabsorption when the same dose is given in different dosage forms or bydifferent routes of administration, or in different carrier systems. The"Synchron" Carrier System has the added advantage compared to otheravailable prolonged-release vehicles employed in dosage forms insofar asit will not release the drug in a dumping action and prevents thepotential hazard of over-dosage if all the drug is released at one timeand is rapidly absorbed. The method for determining sustaining dose withthe present carrier system may be expressed by the formula:

    D×0.693×SV/L.sub.1/2

wherein D is the normal therapeutic dose, SV is the number of hoursdesired to extend the duration of action, and L_(1/2) is the drug'shalf-life. The primary difference between the use of my "Synchron"Carrier System and other sustained-release vehicles is that thedissolution of the vehicle is not dependent upon the pH or the enzymaticactivity of the intestinal fluids. Site action predetermination ispossible via the concentration of the vehicle in the dosage form.

What is claimed is:
 1. A shaped and compressed sustained releasetherapeutic composition comprising a therapeutically active medicamentand a carrier base material, characterized by a long-lasting slow andregular incremental release of the medicament upon administration,wherein the carrier base material is hydroxypropylmethylcellulose or amixture of hydroxypropylmethylcellulose and either up to 30%ethylcellulose or 30% sodium carboxymethylcellulose or both, and whereinthe hydroxypropylmethylcellulose or the mixtures thereof have beensubjected to hydrolysis and oxidation and have a carbonyl content whichranges from 0.2 to 3.0 grams/100 grams and a carboxyl content whichranges from 0.37 to 2.6 grams/100 grams, the oxidation having beencarried out at about 30° to 50° C. in the presence of oxygen or a streamof air for a period of time sufficient to obtain the desired carbonyland carboxyl values and the composition having incorporated therein0.1-1.0%, based on the weight of the carrier material, of a reducingstabilizing agent which prevents undesired further oxidation and thehydrolysis having been carried out either (a) by humidification in achamber at ambient or elevated temperature until the humidity of thechamber reaches at least 85% and the humidity is maintained for at least12 hours or (b) by mixing the carrier base material with water andheating to a temperature of 30°-100° C. for at least 12 hours.
 2. Acomposition according to claim 1 wherein the carbonyl content is in therange of 0.2-3.0 grams/100 grams.
 3. A composition according to claim 1wherein the carboxyl content is in the range of 0.37-2.6 grams/100grams.
 4. A composition according to claim 1 wherein the carbonylcontent is in the range of 0.2-2.0 grams/100 grams and the carboxylcontent is in the range of 0.37-2.6 grams/100 grams.
 5. A compositionaccording to claim 1 wherein the subjection of the carrier base materialto hydrolysis and oxidation is successive or concurrent.
 6. Acomposition according to claim 4 wherein hydrolysis and oxidation arecarried out concurrently by the treatment of the carrier base materialwith air or oxygen containing a sufficient amount of water at anelevated temperature.
 7. A composition according to claim 1 wherein theshaped composition is in unit dosage form.
 8. A composition according toclaim 1 wherein the carrier base material ishydroxypropylmethylcellulose.
 9. A composition according to claim 1 inwhich the stabilizing agent is ascorbyl stearate or palmitate or sodiummetabisulfite.